From Manju Bala, St Christopher’s Hospital for Children. Need help with interpreting a coagulation dilemma. A child, 4 months old, post cardiac surgery, no meds, use of bovine thrombin during surgery with prolonged prothrombin time (PT), 29.9s; partial thromboplastin time (PTT, APTT),107.7s; and thrombin time (TT), 40.4s; no correction on mixing. FII, 25%; FV, 7%, increasing with dilution; FVIII, 129%; FIX, 39%; FX, 69% and FXI, 50%. The latter four factors, although normal appear to increase on dilution like an inhibitor. No evidence of bleeding, no evidence of thrombosis, liver function tests normal. Could this be due to an antibody to bovine thrombin or lupus anticoagulant? Testing is pending.
Hello, Manju Bala, and thank you for your question. Yes, these results seem to reflect the presence of an anti bovine thrombin alloantibody. These IgG antibodies arise following the use of bovine thrombin-based fibrin glue in surgery and typically neutralized factors II and V. Because II and V are in the common pathway, the PT, PTT, and TT are prolonged. Their prolongation variably affects the results of all factor assays, as the assay are based upon either the PT or the PTT. There is a comprehensive discussion of antibodies to bovine thrombin in Kruse-Jarres R, Leissinger CA. Chapter 6: Acquired Coagulation Disorders Caused by Inhibitors in Kitchens CS, Kessler CM, Konkle BA. Consultative Hemostasis and Thrombosis, 3rd Edition, Elsevier, 3rd Edition, page 85.
About one third of patients with these antibodies experience bleeding, however in these patients, the bleeding may be severe. The most effective treatment seems to be platelet concentrate, as platelets provide ample factor V that is bound to platelet membranes and may partially escape antibody neutralization. The antibodies spontaneously disappear after 2–3 months. Fibrin glue that uses recombinant human thrombin (rFII) is now available. This preparation does not cause antibody formation.
You are, of course, wise to pursue the differential diagnosis by assaying for lupus anticoagulant and disseminated intravascular coagulation. It may be that the dilute Russell viper venom time (DRVVT) screen and confirm system could provide interpretable, albeit prolonged results, whereas the PTT-based methods may be confounded by the antibody.
The report of 3 pediatric cases with transient FV antibodies
The report of 3 pediatric cases with transient FV antibodies development after topical bovine exposure from our hospital is suggesting:
“…Factor V inhibitors are known to mimic lupus
anticoagulant since they bind to the phospholipid-binding site of factor V in the second C-type domain of the protein. Two cases had positive lupus anticoagulant by both DRVVT and hexagonal phase phospholipid neutralization test at the time of the diagnosis of factor V inhibitor. However, after factor V inhibitor was no longer detectable, lupus anticoagulant tests became negative. Therefore, the positive lupus anticoagulant results in these cases were most likely false positive…”
Bomgaars L, et al. Development of factor V and thrombin inhibitors in children following bovine thrombin exposure during cardiac surgery: a report of three cases. Congenit Heart Dis. 2010 May-Jun;5(3):303-8
In a paper from Australian colleagues Favaloro et al “Factor
In a paper from Australian colleagues Favaloro et al “Factor V Inhibitors: rare or not so uncommon?A multilaboratory investigation in Blood Coagulation and Fibrinolysis 2004 15:637, in which the case histories of 14 acquired FV Inhibitors were presented, there seemed to be an apparent association with antiphospholipid antibodies in many of the cases.